Pharmacogenomics of Statin Therapy

他汀类药物治疗的药物基因组学

• 批准号: 10293025
• 负责人: RONALD M KRAUSS
• 金额: $ 117.4万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-07 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10293025
• 关键词: Pharmacogenomics; Statin; Therapy

 DESCRIPTION (provided by applicant): The overall objective of the Center "Pharmacogenomics of Statin Therapy" (POST) is to apply genomic, transcriptomic, and metabolomic analyses, together with studies in cellular and animal models, and innovative informatic tools, to identify and validate biomarkers for efficacy of statin drugs in reducing riskof cardiovascular disease (CVD), and for adverse effects of statins, specifically myopathy and type 2 diabetes. This multidisciplinary approach is enabled by a team of investigators with expertise in genomics (human, mouse, and molecular), statistics and informatics, and clinical medicine and pharmacology. The Center is comprised of three Projects, two Research Cores, and an Administrative Core. A major aim of Project 1 is the identification of cellular transcriptomic and metabolomic markers for clinical efficacy and adverse effects of statins. This will be accomplished by analyses in statin-exposed lymphoblast cell lines derived from patients with major adverse coronary events, or onset of myopathy or type 2 diabetes on statin treatment, compared with unaffected statin- treated controls. In addition, using genome wide genotypes from these patients, DNA variants will be identified that are associated with statin-induced changes in the transcripts and metabolites that most strongly discriminate affected patients and controls. Project 2 will use a unique, well-characterized panel of 100 inbred mouse strains to discover genetic variation associated with statin-induced myopathy and dysglycemia. Mechanisms underlying these effects will be investigated, with emphasis on the role of dysregulation of autophagy by statin treatment. Projects 1 and 2 will also use relevant cellular and mouse models, respectively, to perform functional studies to validate effects of genes identified in all POST projects as strong candidates for modulating statin efficacy or adverse effects. In Project 3, information derived from genome-wide genotypes, electronic health records, and pharmacy data in a very large and diverse population-based patient cohort will be leveraged to identify and replicate genetic associations with statin efficacy (lipid lowering and CVD event reduction) and adverse effects (myopathy and type 2 diabetes), as well as to assess the overall heritability of these responses. The Clinical Core, based in Kaiser Permanente of Northern California, will provide the clinical information and biologic materials for both Projects1 and 3. Investigators in the Informatics Core will optimize data analysis and integration of results across all projects. The Administrative Core will provide scientific leadership and management of the Center, and foster scientific interactions and training opportunities. Overall, the research program of this Center provides an innovative model for a "systems" approach to pharmacogenomics that incorporates complementary investigative tools to discover and validate genetically influenced determinants of drug response. Moreover, the findings have the potential for guiding more effective use of statins for reducing CVD risk and minimizing adverse effects, and identifying biomarkers of pathways that modulate the multiple actions of this widely used class of drugs.

 描述（申请人提供）：他汀类药物治疗药物基因组学中心（POST）的总体目标是应用基因组学，转录组学和代谢组学分析，以及细胞和动物模型研究，以及创新的信息学工具，以识别和验证他汀类药物降低心血管疾病（CVD）风险的疗效生物标志物，以及他汀类药物的不良反应，特别是肌病和2型糖尿病。这种多学科的方法是由一组具有基因组学（人类，小鼠和分子），统计学和信息学以及临床医学和药理学专业知识的研究人员实现的。该中心由三个项目，两个研究核心和一个行政核心组成。项目1的主要目的是鉴定他汀类药物临床疗效和不良反应的细胞转录组学和代谢组学标志物。这将通过分析他汀类药物暴露的淋巴母细胞系来实现，这些细胞系来源于接受他汀类药物治疗的重大不良冠状动脉事件或肌病发作或2型糖尿病患者，与未受影响的他汀类药物治疗对照组进行比较。此外，使用来自这些患者的全基因组基因型，将鉴定与他汀类药物诱导的转录物和代谢物变化相关的DNA变异体，这些变异体最能强烈区分受影响的患者和对照。项目2将使用一个独特的，充分表征的100个近交系小鼠品系的小组，以发现与他汀类药物诱导的肌病和肌营养不良相关的遗传变异。这些影响的机制将进行调查，重点是他汀类药物治疗的自噬失调的作用。项目1和2还将分别使用相关的细胞和小鼠模型进行功能研究，以验证所有POST项目中确定的基因的作用，作为调节他汀类药物疗效或不良反应的强有力候选者。在项目3中，将利用来自一个非常大且多样化的基于人群的患者队列中的全基因组基因型、电子健康记录和药房数据的信息来识别和复制与他汀类药物疗效（降脂和CVD事件减少）和不良反应（肌病和2型糖尿病）的遗传相关性，并评估这些反应的总体遗传性。位于北方加州Kaiser Permanente的临床中心将为项目1和项目3提供临床信息和生物材料。信息学核心的研究人员将优化数据分析和结果整合 在所有项目中。行政核心将为中心提供科学的领导和管理，并促进科学互动和培训机会。总体而言，研究 该中心的项目为药物基因组学的“系统”方法提供了一个创新模型，该模型结合了互补的调查工具来发现和验证受遗传影响的药物反应决定因素。此外，这些发现有可能指导更有效地使用他汀类药物来降低CVD风险和最大限度地减少不良反应，并确定调节这类广泛使用的药物的多种作用的途径的生物标志物。

项目成果

How powerful are summary-based methods for identifying expression-trait associations under different genetic architectures?

• DOI: 10.1142/9789813235533_0021
• 发表时间: 2018-01
• 期刊: Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing
• 作者: Y. Veturi;M. Ritchie

Identifying subtype-specific associations between gene expression and DNA methylation profiles in breast cancer.

• DOI: 10.1186/s12920-017-0268-z
• 发表时间: 2017-05-24
• 期刊: BMC medical genomics
• 影响因子: 2.7
• 作者: Lee G;Bang L;Kim SY;Kim D;Sohn KA
• 通讯作者: Sohn KA

A large electronic-health-record-based genome-wide study of serum lipids.

• DOI: 10.1038/s41588-018-0064-5
• 发表时间: 2018-03
• 期刊: Nature genetics
• 影响因子: 30.8
• 作者: Hoffmann TJ;Theusch E;Haldar T;Ranatunga DK;Jorgenson E;Medina MW;Kvale MN;Kwok PY;Schaefer C;Krauss RM;Iribarren C;Risch N
• 通讯作者: Risch N

ZNF542P is a pseudogene associated with LDL response to simvastatin treatment.

• DOI: 10.1038/s41598-018-30859-y
• 发表时间: 2018-08-20
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Kim K;Theusch E;Kuang YL;Dose A;Mitchel K;Cubitt C;Chen YI;Krauss RM;Medina MW
• 通讯作者: Medina MW

Identification of epigenetic interactions between miRNA and DNA methylation associated with gene expression as potential prognostic markers in bladder cancer.

• DOI: 10.1186/s12920-017-0269-y
• 发表时间: 2017-05-24
• 期刊: BMC medical genomics
• 影响因子: 2.7
• 作者: Shivakumar M;Lee Y;Bang L;Garg T;Sohn KA;Kim D
• 通讯作者: Kim D